Each Salmex 50 microgram /500 microgram /dose contains approximately 12.9 mg of lactose

Transcription

1 1. NAME OF THE MEDICINAL PRODUCT Salmex 50 microgram /100 microgram /dose inhalation powder, pre-dispensed Salmex 50 microgram /250 microgram /dose inhalation powder, pre-dispensed Salmex 50 microgram /500 microgram /dose inhalation powder, pre-dispensed 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 45 micrograms of salmeterol (as salmeterol xinafoate) and 93, 233 or 465 micrograms of fluticasone propionate. This corresponds to a pre-dispensed dose of 50 micrograms of salmeterol (as salmeterol xinafoate) and 100, 250 or 500 micrograms fluticasone propionate. Excipient(s) with known effect: Each Salmex 50 microgram /100 microgram /dose contains approximately 13.3 mg of lactose monohydrate. Each Salmex 50 microgram /250 microgram /dose contains approximately 13.2 mg of lactose monohydrate. Each Salmex 50 microgram /500 microgram /dose contains approximately 12.9 mg of lactose monohydrate. For the full list of excipients, see section PHARMACEUTICAL FORM Inhalation powder, pre-dispensed. Moulded plastic device containing a foil strip with 60 regularly placed blisters. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Asthma Salmex is indicated in the regular treatment of asthma where use of a combination product (longacting β 2 agonist and inhaled corticosteroid) is appropriate: - patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled shortacting β 2 agonist or - patients already adequately controlled on both inhaled corticosteroid and long-acting β 2 agonist Note: Salmex 50 microgram /100 microgram strength is not appropriate in adults and children with severe asthma. Chronic Obstructive Pulmonary Disease (COPD) Salmex is indicated for the symptomatic treatment of patients with COPD, with a FEV 1 <60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy. 4.2 Posology and method of administration Posology Route of administration: Inhalation use.

2 Patients should be made aware that Salmex must be used daily for optimum benefit, even when asymptomatic. Patients should be regularly reassessed by a doctor, so that the strength of Salmex they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with the lowest strength of the combination given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a longacting β 2 agonist could be titrated to Salmex given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once daily dosing when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly daytime symptoms the dose should be given in the morning. Patients should be given the strength of Salmex containing the appropriate fluticasone propionate dosage for the severity of their disease. If an individual patient should require dosages outside the recommended regimen, appropriate doses of β 2 agonist and/or corticosteroid should be prescribed. Recommended Doses: Asthma Adults and adolescents 12 years and older: - One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. or - One inhalation of 50 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily. or - One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily. A short-term trial of Salmex may be considered as initial maintenance therapy in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is one inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important. A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial maintenance therapy when one or two of the criteria of severity are missing. In general inhaled corticosteroids remain the first line treatment for most patients. Salmex is not intended for the initial management of mild asthma. Salmex 50 microgram/100 micrograms strength is not appropriate in adults and children with severe asthma; it is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed-combination can be used in patients with severe asthma. Paediatric population Children 4 years and older: - One inhalation of 50 micrograms salmeterol and 100 micrograms fluticasone propionate twice daily. The maximum licensed dose of fluticasone propionate delivered by Salmex in children is 100 microgram twice daily. There are no data available for use of Salmex in children aged under 4 years. COPD Adults: - One inhalation of 50 micrograms salmeterol and 500 micrograms fluticasone propionate twice daily.

3 Special patient groups There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available for use of Salmex in patients with hepatic impairment. Using the inhaler device The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed round it. The dose can then be inhaled and the device closed. For detailed instructions for use see Package leaflet. 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section Special warnings and precautions for use Salmex should not be used to treat acute asthma symptoms for which a fast- and short- acting bronchodilator is required. Patients should be advised to have their inhaler to be used for relief in an acute asthma attack available at all times. Patients should not be initiated on Salmex during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma. Serious asthma-related adverse events and exacerbations may occur during treatment with Salmex. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Salmex. Increased requirements for use of reliever medication (short-acting bronchodilators), or decreased response to reliever medication indicate deterioration of control and patients should be reviewed by a physician. Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. Consideration should be given to increasing corticosteroid therapy. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Salmex. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Salmex should be used (see section 4.2). For patients with COPD experiencing exacerbations, treatment with systemic corticosteroids is typically indicated, therefore patients should be instructed to seek medical attention if symptoms deteriorate with Salmex. Treatment with Salmex should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician. As with all inhaled medication containing corticosteroids, Salmex should be administered with caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway. Appropriate treatment should be promptly instituted, if indicated. Rarely, Salmex may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Salmex should be used with caution in patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

4 There have been very rare reports of increases in blood glucose levels (see section 4.8) and this should be considered when prescribing to patients with a history of diabetes mellitus. As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Salmex should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. The pharmacological side effects of β 2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Salmex contains lactose monohydrate up to 13.5 milligram /dose. This amount does not normally cause problems in lactose intolerant people. The excipient lactose contains small amounts of milk proteins, which may cause allergic reactions. Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see Paediatric population sub-heading below for information on the systemic effects of inhaled corticosteroids in children and adolescents). It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained. Visual disturbance Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. Situations, which could potentially trigger acute adrenal crisis include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Therefore these patients should be treated with special care and adrenocortical function regularly monitored. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures. Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

5 Pneumonia in patients with COPD An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies. There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD. Data from a large clinical trial (the Salmeterol Multi-Center Asthma Research Trial, SMART) suggested African-American patients were at increased risk of serious respiratory-related events or deaths when using salmeterol compared with placebo (see section 5.1). It is not known if this was due to pharmacogenetic or other factors. Patients of black African or Afro-Caribbean ancestry should therefore be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen whilst using salmeterol and fluticasone propionate. Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should therefore be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment (see section 4.5). Paediatric population Children and adolescents <16 years taking high doses of fluticasone propionate (typically 1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, acute adrenal crisis and growth retardation in children and adolescents and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the child or adolescent to a paediatric respiratory specialist. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained. 4.5 Interaction with other medicinal products and other forms of interaction β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from β 2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics. Concomitant use of other β adrenergic containing drugs can have a potentially additive effect. Fluticasone Propionate Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.

6 In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects. In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, and moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided. Salmeterol Potent CYP3A4 inhibitors Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone (see section 4.4). Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of salmeterol or increase salmeterol accumulation with repeat dosing. The concomitant administration of ketoconazole should be avoided, unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir). Moderate CYP 3A4 inhibitors Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold C max and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects. 4.6 Fertility, pregnancy and lactation Fertility There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility. Pregnancy A moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after administration of β 2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

7 Administration of Salmex to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women. Breastfeeding It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk. Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats. A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Salmex therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. 4.7 Effects on ability to drive and use machines Salmex has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects As Salmex contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds. Adverse events which have been associated with salmeterol/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1000 to <1/100), rare ( 1/10,000 to <1/1000) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in placebo was not taken into account. System Class Infections Infestations Organ & Adverse Event Candidiasis of the mouth and throat Pneumonia (in COPD patients) Bronchitis Oesophageal candidiasis Frequency Common Common1, 3, 5 Common 1, 3 Rare Immune System Disorders Endocrine Disorders Metabolism & Nutrition Disorders Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema) Respiratory symptoms (dyspnoea) Respiratory symptoms (bronchospasm) Anaphylactic reactions including anaphylactic shock Cushing's syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Hypokalaemia Hyperglycaemia Rare Rare Rare Rare 4 Common 3 4

8 System Class Psychiatric Disorders Nervous System Disorders Eye Disorders Organ Cardiac Disorders Respiratory, Thoracic & Mediastinal Disorders Skin and subcutaneous tissue disorders Musculoskeletal & Connective Tissue Disorders Adverse Event Anxiety Sleep disorders Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children) Depression, aggression (predominantly in children) Headache Tremor Cataract Glaucoma Vision, blurred (see also section 4.4) Palpitations Tachycardia Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles). Atrial fibrillation Angina pectoris Nasopharyngitis Throat irritation Hoarseness/dysphonia Sinusitis Paradoxical bronchospasm Frequency Rare Not known Very Common 1 Rare 4 Not known Rare Very Common 2, 3 Common Common Common 1, 3 Rare 4 Contusions Common 1, 3 Muscle cramps Traumatic fractures Arthralgia Myalgia 1. Reported commonly in placebo 2. Reported very commonly in placebo 3. Reported over 3 years in a COPD study 4. See section See section 5.1. Common Common 1, 3 Common Common Description of selected adverse reactions The pharmacological side effects of β 2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Salmex should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat and, rarely, of the oesophagus can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by rinsing the mouth with water and/or brushing the teeth after using the

9 product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Salmex. Paediatric population Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression and growth retardation in children and adolescents (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose There are no data available from clinical trials on overdose with Salmex, however data on overdose with both drugs are given below: The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If Salmex therapy has to be withdrawn due to overdose of the β agonist component of the drug, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered. Acute: Acute inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements. Chronic overdose of inhaled fluticasone propionate: Adrenal reserve should be monitored and treatment with a systemic corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. Refer to section 4.4: risk of adrenal suppression. In cases of both acute and chronic fluticasone propionate overdose, Salmex therapy should be continued at a suitable dosage for symptom control. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Adrenergics in combination with corticosteroids or other drugs, excl. Anticholinergics., ATC code: R03AK06 Mechanism of action and pharmacodynamic effects Salmex contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) β 2 adrenoceptor agonist with a long side chain which binds to the exosite of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β 2 agonists.

10 Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid antiinflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, with less adverse effects than when corticosteroids are administered systemically. Clinical efficacy and safety Salmeterol and fluticasone propionate clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of salmeterol and fluticasone propionate versus inhaled corticosteroid (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with salmeterol and fluticasone propionate achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose. *Well controlled asthma was achieved more rapidly with salmeterol and fluticasone propionate than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well controlled week was 16 days for salmeterol and fluticasone propionate compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual well controlled week was 16 days in the salmeterol and fluticasone propionate treatment compared to 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment Salmeterol/FP FP WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS ( 500 micrograms 75% 44% 60% 28% BDP or equivalent/day) Medium dose ICS (>500 to % 29% 47% 16% micrograms BDP or equivalent/day) Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom score 1 defined as 'symptoms for one short period during the day'), SABA use on less than or equal to 2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that salmeterol and fluticasone propionate 50/100 micrograms bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2). A double blind, randomised, parallel group study in 318 patients with persistent asthma aged 18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of salmeterol and fluticasone propionate for two weeks. The study showed that doubling the inhalations of each strength of salmeterol and fluticasone propionate for up to 14 days resulted in a small increase in β agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid-related

11 adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in β agonist-related adverse events should be taken into account if doubling the dose of salmeterol and fluticasone propionate is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Salmeterol and fluticasone propionate COPD clinical trials TORCH was a 3-year study to assess the effect of treatment with salmeterol and fluticasone propionate 50/500 micrograms bd, salmeterol 50 micrograms bd, fluticasone propionate (FP) 500 micrograms bd or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (prebronchodilator) FEV 1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all cause mortality at 3 years for salmeterol and fluticasone propionate vs Placebo. All cause mortality at 3 years Number of deaths (%) Hazard Ratio vs Placebo (CIs) p value Hazard Ratio salmeterol and fluticasone propionate 50/500 vs components (CIs) p value Placebo N = 1524 Salmeterol 50 N = (15.2%) (13.5%) N/A (0.73, 1.06) N/A (0.77, 1.13) FP 500 N = (16.0%) (0.89, 1.27) (0.64, 0.93) salmeterol and fluticasone propionate 50/500 N = (12.6%) (0.68, 1.00 ) N/A 1. Non-significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status There was a trend towards improved survival in subjects treated with salmeterol and fluticasone propionate compared with placebo over 3 years however this did not achieve the statistical significance level p The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for salmeterol and fluticasone propionate. The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol and fluticasone propionate as compared with treatment with salmeterol, FP and placebo (mean rate in the salmeterol and fluticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively. Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for salmeterol and fluticasone propionate compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant.

12 The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for salmeterol and fluticasone propionate (Hazard ratio for salmeterol and fluticasone propionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia-related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for salmeterol and fluticasone propionate. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% salmeterol and fluticasone propionate; Hazard ratio for salmeterol and fluticasone propionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p= Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of salmeterol and fluticasone propionate 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO were randomised, double blind, parallel group, replicate studies comparing the effect of salmeterol and fluticasone propionate 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV 1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (β 2 agonist and anticholinergic), ipratropium/salbutamol combination products, oral β 2 agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with salmeterol and fluticasone propionate 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and predose morning (AM) FEV 1 ) significantly favoured salmeterol and fluticasone propionate 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the salmeterol and fluticasone propionate 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in salmeterol and fluticasone propionate 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol and fluticasone propionate 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with salmeterol and fluticasone propionate 50/500 micrograms bd in TORCH. The Salmeterol Multi-center Asthma Research Trial (SMART) SMART was a multi-centre, randomised, double blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if 12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences.

13 Key findings from SMART: primary endpoint Patient group Number of primary endpoint events /number of patients Relative Risk (95% confidence salmeterol placebo intervals) All patients 50/13,176 36/13, (0.91, 2.14) Patients using inhaled steroids 23/6,127 19/6, (0.66, 2.23) Patients not using inhaled 27/7,049 17/7, (0.87, 2.93) steroids African-American patients 20/2,366 5/2, (1.54, 10.90) (Risk in bold is statistically significant at the 95% level.) Key findings from SMART by inhaled steroid use at baseline: secondary endpoints Number of secondary endpoint events /number of patients salmeterol placebo Relative Risk (95% confidence intervals) Respiratory-related death Patients using inhaled steroids 10/6127 5/ (0.69, 5.86) Patients not using inhaled steroids 14/7049 6/ (0.88, 5.94) Combined asthma-related death or life-threatening experience Patients using inhaled steroids 16/ / (0.60, 2.58) Patients not using inhaled steroids 21/7049 9/ (1.10, 5.22) Asthma-related death Patients using inhaled steroids 4/6127 3/ (0.30, 6.04) Patients not using inhaled steroids 9/7049 0/7041 * (*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all cause death or lifethreatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population. Paediatric population In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of salmeterol/fluticasone propionate is equally efficacious to doubling the dose of fluticasone propionate regarding symptom control and lung function. This study was not designed to investigate the effect on exacerbations. In a 12 week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/fluticasone propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as improvements in symptom score and rescue salbutamol use. There were no differences between the 2 treatment arms. There were no differences in safety parameters between the 2 treatment arms. In a 12 week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary objective. Children received either salmeterol/fluticasone propionate (50/100 micrograms) or fluticasone propionate (100 micrograms) alone twice daily. Two children on salmeterol/fluticasone propionate and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12 weeks no children in either treatment arm had abnormally low 24 hour urinary cortisol excretion. There were no other differences in safety profile between the treatment arms. 5.2 Pharmacokinetic properties For pharmacokinetic purposes each component can be considered separately.

14 Salmeterol Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram /ml or less) achieved after inhaled dosing. Fluticasone propionate The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5 to 11% of the nominal dose depending on the inhalation device used. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of fluticasone propionate is characterised by high plasma clearance (1150 ml/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of approximately 8 hours. Plasma protein binding is 91%. Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces. The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug. Paediatric population In a population pharmacokinetic analysis utilising data from 9 controlled clinical trials with different devices (Diskus metered dose inhaler) that included 350 patients with asthma aged 4 to 77 years (174 patients 4 to 11 years of age) higher fluticasone propionate systemic exposure following treatment with Salmeterol and fluticasone propionate Diskus 50/100 compared to fluticasone propionate Diskus 100 were seen. Geometric Mean Ratio [90% CI] for the Salmeterol/fluticasone propionate vs. fluticasone propionate Diskus Comparison in Children and Adolescent/Adult Populations Treatment (test vs. ref) Population AUC C max Salmeterol/ fluticasone propionate Diskus 50/100 fluticasone propionate Diskus100 Children (4 11yr) 1.20 [ ] 1.25 [ ] Salmeterol/fluticasone propionate Diskus 50/100 fluticasone propionate Diskus 100 Adolescent/Adult ( 12yr) 1.52 [ ] 1.52 [ ] The effect of 21 days of treatment with Salmeterol and fluticasone propionate Inhaler 25/50 micrograms (2 inhalations twice daily with or without a spacer) or Salmeterol and fluticasone propionate Diskus 50/100 micrograms (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol Inhaler was similar for Salmeterol and fluticasone propionate Inhaler, Salmeterol and fluticasone propionate with spacer, and Salmeterol and fluticasone propionate (126 pg hr/ml [95% CI: 70, 225], 103 pg hr/ml [95% CI: 54, 200], and 110 pg hr/ml [95% CI: 55, 219], respectively). Systemic exposure to fluticasone propionate was similar for

15 Salmeterol and fluticasone propionate Inhaler with spacer (107 pg hr/ml [95% CI: 45.7, 252.2]) and Salmeterol and fluticasone propionate Diskus (138 pg hr/ml [95% CI: 69.3, 273.2]), but lower for Salmeterol and fluticasone propionate Inhaler (24 pg hr/ml [95% CI: 9.6, 60.2]). 5.3 Preclinical safety data The only safety concerns for human use derived from animal studies of salmeterol and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions. In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol have shown embryofetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Excipient: Lactose monohydrate (which contains milk proteins). 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store at temperatures below 30 C, in the original package to protect from moisture. 6.5 Nature and contents of container Blister OPA/Aluminium/ PVC/Aluminium/PET/paper placed in the inhaler equipped with a mouthpiece and dose counter. The inhaler in a cardboard box. 1dose inhaler contains 60 doses. The plastic devices are available in cardboard containers, which hold 1 x 60 dose, 2 x 60 dose, 3x 60 dose, 10 x 60 dose Salmex Not all pack sizes may be marketed. 6.6 Special precautions for disposal <and other handling> Salmex releases a powder which is inhaled into the lungs. A dose indicator on Salmex indicates the number of doses left. For detailed instructions for use see the Patient Information Leaflet. 7. MARKETING AUTHORISATION HOLDER Glenmark Pharmaceuticals Europe Limited Laxmi House, 2B Draycott Avenue, Kenton, Middlesex HA3 0BU, United Kingdom Telephone:+44 (0)

16 Telefax:+44 (0) MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION <Date of first authorisation: {DD month YYYY}> <Date of latest renewal: {DD month YYYY}> 10. DATE OF REVISION OF THE TEXT